Schizophrenia is a psychosis marked by withdrawn, bizarre, and sometime delusional behavior. About 1% of the United States population, 2,400,000 people, suffer from the disease. The estimated medical costs in the United States for treatment of schizophrenia run as high as $40 billion a year.
Several classes of drugs are currently marketed for use in the symptomatic treatment of psychoses. Certain antipsychotics, referred to as neuroleptics, are known to produce unwanted extrapyramidal side effects, including acute dystonia, akathisia, parkinsonian syndrome, anticholinergic effects, hypotension, increased prolactin levels, malignant syndrome, perioral tremor, and tardive dyskinesia. The parkinsonian syndrome and tardive dyskinesia side effects are thought to be mediated by the antagonist effect of the drug on dopamine receptors (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, 1990). Tardive dyskinesia, an often irreversible syndrome consisting of involuntary movement or rigidity of the muscles, is caused by standard neuroleptics at an estimated rate of 4 cases per 100 patient years of treatment.
Because of the limitations of currently available antipsychotic drugs, the search continues for compounds with fewer deleterious side effects and better efficacy (Abou-Gharbia and Moyer, "Novel Antipsychotic Agents", in Annual Reports in Medicinal Chemistry, Volume 25, pp 1-10, Academic Press, 1990).
Effective neuroleptics include the phenothiazine derivatives chlorpromazine hydrochloride (Thorazine), triflupromazine hydrochloride (Vesprin), mesoridazine besylate (Serentil), thioridazine hydrochloride (Mellaril, Millazine), acetophenazine maleate (Tindal), fluphenazine (Permitil, Prolixin), perphenazine (Trilafon), trifluoperazine hydrochloride (Stelazine, Suprazine), chlorprothixene (Taractan), and thiothixene hydrochloride (Navane). Other antipsychotics include haloperidol and haloperidol decanoate (Haldol, Halperon), loxapine succinate (Loxitane), molindone hydrochloride (Moban), and pimozide (Orap). The pharmacology of these drugs is reviewed in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, 1990 and in Physicians' Desk Reference, 45th Edition, Medical Economics, 1991.
Antipsychotics also include "atypical" antipsychotics, such as the dibenzodiazepine clozapine (Clozaril), which have little extrapyramidal side effects.
Neuroleptic drugs, which are the primary antipsychotic drugs used in the treatment of schizophrenia, are thought to exert their therapeutic effects by binding to and blocking dopamine receptors, primarily D.sub.2 receptors (Snyder and Largent (1989) J. Neuropsychiatry 1:7-15). Most marketed antipsychotics are neuroleptics and are referred to as dopamine receptor antagonist antipsychotics. Some neuroleptics, such as cinuperone, tiospirone, and haloperidol, are known to nonselectively antagonize both sigma and dopamine D.sub.2 receptors (Snyder and Largent (1989) J. Neuropsychiatry 1:7-15).